Prevention of Hemodialysis Vascular Access Stenosis

预防血液透析血管通路狭窄

• 批准号: 7690353
• 负责人: Alfred K Cheung
• 金额: $ 110.4万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7690353
• 关键词: 3-Dimensional; Address; Algorithms; Anastomosis - action; Animal Experiments; Animals; Area; Arteries; Biomedical Engineering; Blood Vessels; Canis familiaris; Cell Culture Techniques; Characteristics; Clinical; Clinical Medicine; Clinical Research; Clinical Trials; Computer Assisted; Computer Systems Development; Data; Development; Dialysis procedure; Diffusion; Dipyridamole; Discipline; Drug Delivery Systems; Drug Kinetics; Drug Transport; Drug usage; Elements; Failure; Family suidae; Funding; Future; Gel; Goals; Grant; Hemodialysis; Hyperplasia; Image; Imaging Techniques; In Vitro; Individual; Industry; Institutes; Lesion; Magnetic Resonance Angiography; Medical Device; Medicine; Methods; Microspheres; Modeling; Monitor; Morphology; Outcome; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacology and Toxicology; Pharmacy (field); Physiologic arteriovenous anastomosis; Polymers; Polytetrafluoroethylene; Postdoctoral Fellow; Preparation; Prevention; Property; Published Comment; Radiology Specialty; Research; Research Personnel; Safety; Sirolimus; Stenosis; Students; System; Testing; Therapeutic; Thrombosis; Tissue Model; Tissues; Training; Translating; United States National Institutes of Health; Utah; Validation; Vascular Graft; Veins; Venous; Work; X-Ray Computed Tomography; antiproliferative drugs; base; complex biological systems; copolymer; design; drug efficacy; imaging modality; in vivo; innovation; local drug delivery; mathematical model; meetings; multidisciplinary; novel; pharmacokinetic model; prevent; programs; reconstruction; scientific computing; success; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Stenosis caused by neointimal hyperplasia (NH) often occurs focally at the anastomoses of arteriovenous (AV) grafts used for hemodialysis, leading to thrombosis and occlusion. This is a competitive renewal resubmission for a project to develop novel sustained drug delivery systems that could be injected percutaneously and allow local delivery of anti-proliferative drugs to prevent graft stenosis. The Bioengineering area is "Clinical Medicine, Therapeutics and Drug Delivery". Using a unique polymeric drug depot (ReGel) to deliver paclitaxel perivascularly, we have demonstrated the feasibility of this approach in a canine model. We have now perfected a porcine model and demonstrated the sustained, quantifiable delivery of dipyridamole and rapamycin from the perivascular depot into the vessel walls over weeks. The 4 specific aims in this renewal are to: (1) optimize sustained-release polymer gel systems for local delivery of specific anti-proliferative drugs based on each drug's physicochemical, pharmacokinetic and pharmacodynamic properties; (2) develop and validate finite element models to predict the long-term pharmacokinetics of drugs administered perivascularly using sustained-delivery systems at the anastomoses of AV grafts; (3) identify drugs that are safe and efficacious in preventing stenosis at the graft anastomoses when administered using sustained-delivery systems; (4) adapt and refine 3D imaging modalities, including magnetic resonance angiography (MRA), for more accurate quantification of stenosis progression and drug efficacy at the graft anastomoses in the porcine model. There are 6 Leading Investigators in 5 departments: (1) R. Rathi, MacroMed, Inc. (development of polymers for drug delivery); (2) S. Kern, Depts. of Pharmaceutics and Bioengineering and M. Kirby, Scientific Computing & Imaging Institute (pharmacokinetic modeling and validation in tissues); (3) D. Blumenthal, Dept. of Pharmacology & Toxicology (characterization of in vitro drug efficacy and mechanism of action); (4) A. Cheung, Dept. of Medicine, U. of Utah (animal experiments and clinical correlation) who also serves as the PI and Project Manager; (5) D. Parker, Dept. of Radiology (MRA imaging development and 3D reconstruction of NH morphology). This multidisciplinary team, using an integrative systems approach, is essential for the development of innovative methods to solve an important clinical problem. It will also offer excellent opportunities for trainees of various disciplines to interact with each other in a collaborative manner. It is highly likely that, within this 5-year proposal, the results of this project can be applied to pilot clinical studies.

描述（由申请人提供）：新生内膜增生（NH）引起的狭窄通常局灶性发生在用于血液透析的动静脉（AV）移植物的动脉瘤处，导致血栓形成和闭塞。这是一个项目的竞争性更新重新提交，该项目旨在开发新型持续药物递送系统，该系统可经皮注射，并允许局部递送抗增殖药物以预防移植物狭窄。生物工程领域是“临床医学，治疗和药物输送”。使用一种独特的聚合物药物贮库（ReGel），以提供紫杉醇血管周围，我们已经证明了这种方法在犬模型的可行性。我们现在已经完善了一个猪模型，并证明了持续的，可量化的交付潘生丁和雷帕霉素从血管周围的仓库进入血管壁数周。本次更新的4个具体目标是：（1）根据每种药物的理化、药代动力学和药效学特性，优化用于局部递送特定抗增殖药物的缓释聚合物凝胶系统;（2）开发和验证有限元模型，以预测在AV移植物动脉瘤处使用缓释递送系统进行血管周围给药的药物的长期药代动力学;（3）确定使用持续给药系统给药时安全有效预防移植物狭窄的药物;（4）调整和改进3D成像模式，包括磁共振血管造影（MRA），以更准确地量化猪模型中移植物狭窄的进展和药物疗效。主要研究者6名，分布于5个科室：（1）R. Rathi，MacroMed，Inc.（2）S.克恩省药学与生物工程系和M. Kirby，Scientific Computing & Imaging Institute（组织中的药代动力学建模和验证）;（3）D.布卢门塔尔，部门药理学和毒理学（体外药物功效和作用机制的表征）;（4）A. Cheung，部门美国医学院（动物实验和临床相关性），同时担任PI和项目经理;（5）D.帕克，部门放射学（MRA成像开发和NH形态的3D重建）。这个多学科的团队，使用综合系统的方法，是必不可少的创新方法来解决一个重要的临床问题的发展。它还将为不同学科的学员提供良好的机会，以合作的方式相互交流。在本5年计划中，该项目的结果极有可能应用于试点临床研究。